# Uncovering interactions of the gut microbiome with the immune system in the context of immune checkpoint inhibitors

> **NIH NIH F30** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $39,650

## Abstract

PROJECT SUMMARY/ABSTRACT
Immune checkpoint blockade is a major breakthrough in cancer immunotherapy that promotes the immune
system’s response against tumors. Unfortunately, this immunotherapy is ineffective in the majority of cancer
patients, posing a major clinical problem. The microbial organisms in the gut have a profound influence in
educating the immune system as well as dysregulating the immune system to undermine immunotherapy
success. These gut microbes are manipulatable through microbial transplants or prebiotics/probiotics and thus
offers an practicable way of improving efficacy. This proposal will investigate the mechanisms by which the gut
microbiome influences the human immune system in the context of immune checkpoint inhibitors (ICIs) to
ultimately improve cancer treatment.
Recent advances have shown that the gut microbiome plays an influential role in ICI efficacy, but the underlying
mechanisms are unknown. I hypothesize that it is the microbial metabolites from particular gut
commensals that directly influence immune cell response to ICIs and thus causes the differences seen
in ICI clinical efficacy. From our preliminary experiments, we have identified four commensal gut bacteria that
produce products to directly stimulate human immune cell production of interferon-γ, a central orchestrator of
antitumor immune response. To further investigate how these bacteria alter the immune system to influence ICI
efficacy, I propose two aims. In Aim 1, I will identify the microbial metabolite producing gene responsible for
inducing this immune effect by creating a Fosmid library of the microbial genome of each of these four bacteria.
These clones will be tested in an in-vitro immune assay to identify which part of the microbial genome specifically
influences interferon production. In Aim 2, I will demonstrate the in-vivo effects of these bacteria by transplanting
these four commensal gut bacteria in a model by which healthy mice with a humanized immune system develop
autoimmune symptoms when treated with an ICI. By administering these bacteria and their knockout mutants of
the immunomodulatory metabolite gene in these humanized mouse, we are able to assess the severity of
autoimmune response as a readout of ICI effectiveness. The goal of this project is to find a bacterium that
increases ICI efficacy and identify what gene in the bacterium is producing the immunomodulatory metabolite.
By advancing our understanding of microbiome–immune system interactions, findings from this project are
anticipated to stimulate improvements in clinical ICI treatment protocols. For example, manipulation of a cancer
patient’s gut microbial composition prior to immunotherapy could be a highly advantageous strategy to increase
ICI efficacy.

## Key facts

- **NIH application ID:** 9992634
- **Project number:** 1F30CA247405-01A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Jennifer Chung
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,650
- **Award type:** 1
- **Project period:** 2020-03-15 → 2022-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992634

## Citation

> US National Institutes of Health, RePORTER application 9992634, Uncovering interactions of the gut microbiome with the immune system in the context of immune checkpoint inhibitors (1F30CA247405-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992634. Licensed CC0.

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